A new common functional coding variant at the DDC gene change renal enzyme activity and modify renal dopamine function View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-12

AUTHORS

Jose Pablo Miramontes-Gonzalez, Makena Hightower, Kuixing Zhang, Hiroki Kurosaki, Andrew J. Schork, Nilima Biswas, Sucheta Vaingankar, Manjula Mahata, Michael S. Lipkowitz, Caroline M. Nievergelt, Dewleen G. Baker, Michael G. Ziegler, David León-Jiménez, Rogelio González-Sarmiento, Hiroshi Ichinose, Daniel T. O’Connor

ABSTRACT

The intra-renal dopamine (DA) system is highly expressed in the proximal tubule and contributes to Na+ and blood pressure homeostasis, as well as to the development of nephropathy. In the kidney, the enzyme DOPA Decarboxylase (DDC) originating from the circulation. We used a twin/family study design, followed by polymorphism association analysis at DDC locus to elucidate heritable influences on renal DA production. Dense single nucleotide polymorphism (SNP) genotyping across the DDC locus on chromosome 7p12 was analyzed by re-sequencing guided by trait-associated genetic markers to discover the responsible genetic variation. We also characterized kinetics of the expressed DDC mutant enzyme. Systematic polymorphism screening across the 15-Exon DDC locus revealed a single coding variant in Exon-14 that was associated with DA excretion and multiple other renal traits indicating pleiotropy. When expressed and characterized in eukaryotic cells, the 462Gln variant displayed lower Vmax (maximal rate of product formation by an enzyme) (21.3 versus 44.9 nmol/min/mg) and lower Km (substrate concentration at which half-maximal product formation is achieved by an enzyme.)(36.2 versus 46.8 μM) than the wild-type (Arg462) allele. The highly heritable DA excretion trait is substantially influenced by a previously uncharacterized common coding variant (Arg462Gln) at the DDC gene that affects multiple renal tubular and glomerular traits, and predicts accelerated functional decline in chronic kidney disease. More... »

PAGES

5055

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-019-41504-7

DOI

http://dx.doi.org/10.1038/s41598-019-41504-7

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1112966918

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30911067


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Download the RDF metadata as:  json-ld nt turtle xml License info

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RDF/XML is a standard XML format for linked data.

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